Complement C4/C3 activation products and their receptors play important roles in linking innate with adaptive immunity. Two of these receptors, complement receptor type 1 (CR1/CD35) and type 2 (CR2/CD21), are members of a family of structurally related proteins called the Regulators of Complement Activation (RCA). CR2 and CR1 are expressed in mice on B lymphocytes, follicular dendritic cells and a small subset of T lymphocytes. Previous studies by ourselves and others using inhibitory monoclonal antibodies and gene targeted mice have demonstrated key roles for CR2 and CR1 in the development of humoral and cellular immunity as well as provided substantial evidence for a role in the maintenance of tolerance to certain self antigens. Another class of membrane RCA proteins also interacts with C4/C3 activation fragments, but rather than act as receptors, these molecules function as regulatory proteins to block inappropriate complement activation on self cells. In preliminary studies, we have shown that a model of renal ischemia-reperfusion injury is dependent upon alternative pathway complement activation that is initiated when one membrane RCA regulatory protein designated Crry changes its sub-cellular location away from the site of subsequent complement deposition. In addition, we have identified and characterized a novel role for the receptors CR2 and CR1 in the development of a pathogenic subset of natural antibodies that is critically important to the development of experimental intestinal ischemia-reperfusion injury. Finally, we have identified several novel genes with structural similarities to the RCA family and developed preliminary evidence that at least one of these can encode a complement binding and regulatory protein. We now propose to extend these studies by pursuing the following specific aims: Specific Aim #1: Identify the mechanisms by which the alternative pathway is activated in response to ischemia-reperfusion of the kidney and causes target organ injury. Specific Aim #2: Define the role of CR2/CR1 in the development of the pathogenic natural antibody repertoire that initiates intestinal ischemia-reperfusion injury. Specific Aim #3: Determine the functional activities and biologic relevance of novel SCR-containing candidate C3/C4 binding and regulatory proteins.